Filamentous micro-organisms are widely used as industrial producers of products such as antibiotics, anticancer agents, antifungicides and enzymes (Bennett, 1998; Demain, 1991; Hopwood et al., 1995). These organisms include the eukaryotic filamentous fungi (ascomycetes) and the prokaryotic actinomycetes (e.g. Amycolatopsis, Nocardia, Thermobifido and Streptomyces). The market capitalization for antibiotics and enzymes totals around 28 and 2 billion dollars per year, respectively. The soil-dwelling streptomycete Streptomyces coelicolor constitutes an important model system for the study of bacterial development and antibiotic production (Locci, 1986). Streptomyces colonies form a meshwork of vegetative mycelia from which aerial, spore-forming hyphae differentiate (Chater, 1998). Their morphogenesis is controlled by a complex, spatial and temporal genetic programming scheme that is switched on upon nutrient limitation (Schauer et al., 1988; Willey et al., 1991). Streptomycetes are principal protagonists in the recycling and mineralization of organic compounds of dead plants, fungi and insects, which are composed of the polysaccharides cellulose, xylan, and chitin, the most abundant carbon sources on earth (Hodgson, 2000). Hence, they also play a crucial role in our hunt for renewable sources. Interestingly, the study of genome sequences of actinomycetes has unveiled a surprisingly large number of cryptic antibiotic biosynthesis clusters and novel enzymes with industrial potential, thus offering new challenges for directed discovery of natural products, including drugs and enzymes (Hopwood, 2003). For example, a novel screening technique established that selective growth conditions can induce the normally dormant biosynthetic clusters for enediyne-type anti-tumour antibiotics (Zazopoulos et al., 2003).
Global regulation in bacteria involves the presence of pleiotropic-acting transcription factors that coordinate expression of genes, operons and regulons of diverse cellular processes (Martinez-Antonio and Collado-Vides, 2003). Escherichia coli has seven global transcription factors that together regulate approximately half of its genes. The most prominent one is the cyclic AMP receptor protein Crp directly controlling around 200 target genes (Bruckner and Titgemeyer, 2002; Gosset et al., 2004; Zhang et al., 2005). Crp represents the paradigm of a genetic regulator, its properties having attained textbook status and the Crp-cAMP mediated regulation of alternative carbon sources in E. coli is probably the most classical example to illustrate mechanisms that modulate genes expression. Uncovering such pleiotropic regulators is crucial for our understanding of the life style of bacteria and since the elucidation of the role of Crp in carbon catabolite repression (CCR), scientists devoted to carbon utilization always refers to this model to discuss the situation in other micro-organisms. Hence, the catabolite control protein CcpA is a similarly global regulator in low G+C Gram-positive bacteria, and controls more than 300 genes in Bacillus subtilis (Moreno et al., 2001; Titgemeyer and Hillen, 2002). CcpA controls genes involved in CCR, glycolysis, nitrogen assimilation, and phosphate metabolism (Bruckner and Titgemeyer, 2002).
So far, the study of carbon utilization in streptomycetes failed to discover a global regulator, and only resulted in examples of specific regulators controlling individual sugar regulons (Hindle and Smith, 1994; Parche et al., 1999; van Wezel et al., 1997). Interestingly, streptomycetes privileged another category of regulator/sensor element to globally mediate the shift from CCR to substrate induction, using MsiK as the master switch to provide energy to many sugar-specific ABC transporters (Hurtubise et al., 1995; Schlosser et al., 1997; Schlosser et al., 1999; Schlosser, 2000). However, a conserved regulatory motif identified upstream of few genes related to carbohydrate metabolism was still intriguing the research community devoted to carbon regulation, and maintained the idea that perhaps a global regulator would exist (Nothaft et al., 2003; Rigali et al., 2004; Studholme et al., 2004). Our in silico analysis of the helix-turn-helix GntR family (Rigali et al., 2002) recently identified new cis/trans regulatory codes that predict that DasR (SCO5231) regulates the phosphotransferase system specifically for the uptake of N-acetylglucosamine (PTSNag) (Rigali et al., 2004).